Conformationally restricted hydantoin-based peptidomimetics as inhibitors of caspase-3 with basic groups allowed at the S3 enzyme subsite.

By using a combination of molecular modeling, combinatorial chemistry, and biological essays, novel scaffold molecules for the inhibition of caspase-3 have been developed. These compounds have an overall attenuated negative charge and show similar IC(50) values for both recombinant and human endogenous caspase-3. This might provide the basis for a novel strategy for the discovery of potent and more druglike inhibitors of caspase-3.